Lansoprazole orally disintegrating tablets

Abstract

The invention provides orally disintegrating tablets that readily disintegrates in the mouth, releasing enteric coated drug sub-tablets.

1 . An orally disintegrating tablet, comprising more than one enteric coated sub-tablet, mixed with one or more tablet excipients; wherein 
 the sub-tablets comprise: 
 an inner core, substantially free of any alkaline stabilizing agent, and comprising one or more inert core excipients;  
 an acid sensitive drug in, on, or over the inner core;  
 an inert first coating layer, substantially free of the drug and any alkaline stabilizing agent, disposed over the inner core and the drug;  
 an alkaline stabilizing layer, comprising an alkaline stabilizing agent, disposed over the inner core and the acid sensitive drug; and  
 an acid resistant enteric coating layer, disposed over the alkaline stabilizing layer; wherein  
 the orally disintegrating tablet is formulated to disintegrate when placed in a mouth.  
   
   
   
       2 . The orally disintegrating tablet of  claim 1 , further comprising at least two sub-populations of inner cores, wherein each sub-populations has a different size distribution.  
   
   
       3 . The orally disintegrating tablet of  claim 1 , wherein the acid sensitive drug comprises a Benzimidazole derivative.  
   
   
       4 . The orally disintegrating tablet of  claim 1 , wherein the acid sensitive drug comprises Lansoprazole.  
   
   
       5 . The orally disintegrating tablet of  claim 1 , further comprising a drug layer disposed over the inner core, the drug layer comprising the acid sensitive drug.  
   
   
       6 . The orally disintegrating tablet of  claim 1 , further comprising a drug layer, comprising the acid sensitive drug, disposed over the inner core.  
   
   
       7 . The orally disintegrating tablet of  claim 6 , wherein at least one of the drug layer, the inert first coating layer and the alkaline stabilizing layer comprises at least one of a film forming agent and an excipient.  
   
   
       8 . The orally disintegrating tablet of  claim 1 , wherein the alkaline stabilizing agent comprises a carbonate.  
   
   
       9 . The orally disintegrating tablet of  claim 8 , wherein the carbonate is calcium carbonate, magnesium carbonate, or a mixture thereof.  
   
   
       10 . The orally disintegrating tablet of  claim 1 , wherein the enteric coating comprises at least one of hypromellose phthalate and methacrylic and methacrylate copolymers.  
   
   
       11 . The orally disintegrating tablet of  claim 10 , wherein the methacrylic and methacrylate copolymers are selected from the group consisting of a methacrylic acid copolymer type B, a methacrylic acid copolymer type C, a methacrylic acid, methylmethacrylate, and methylmethacrylate copolymer, a methacrylate copolymer, and mixtures thereof.  
   
   
       12 . The orally disintegrating tablet of  claim 1 , further comprising first and second sub-populations of the inner cores, the inner cores in the first sub-population having smaller diameters than the inner cores of the second population, in a weight ratio the first sub-population to the second sub-population of from about 1:1 to about 4:1.  
   
   
       13 . The orally disintegrating tablet of  claim 12 , wherein the weight ratio is from about 2:1 to about 3:1.  
   
   
       14 . The orally disintegrating tablet of  claim 12 , wherein the acid sensitive drug is Lansoprazole, and the first sub-population has a size distribution of diameters of from about 250 to about 350 μm, and the second sub-population has a size distribution of diameters of from about 400 to about 500 μm.  
   
   
       15 . The orally disintegrating tablet of  claim 1 , wherein the inner core is an extrusion, comprising the acid sensitive drug and 1 or more excipients.  
   
   
       16 . The orally disintegrating tablet of  claim 1 , wherein the orally disintegrating tablet is a compressed tablet comprising the sub-tablets and excipients.  
   
   
       17 . The orally disintegrating tablet of  claim 1 , wherein the tablet excipients comprise at least one of a starch, a cellulose, a hydrated sugar, and silica.  
   
   
       18 . The orally disintegrating tablet of  claim 17 , wherein the starch is maize starch, the cellulose is powdered cellulose, the hydrated sugar is lactose monohydrate, and the silica is colloidal silica.  
   
   
       19 . The orally disintegrating tablet of  claim 1 , wherein the enteric coating layer further comprises at least one of a plasticizer and one or more excipients.  
   
   
       20 . The orally disintegrating tablet of  claim 19 , wherein the excipients comprise at least one of titanium dioxide and talc.  
   
   
       21 . The orally disintegrating tablet of  claim 1 , wherein upon exposure of the sub-tablets to a solution having a pH of about 3.5 for about 20 minutes, no more than about 10 percent by weight of the acid sensitive drug is dissolved by the solution.  
   
   
       22 . The orally disintegrating tablet of  claim 1 , wherein upon exposure of the sub-tablets to a solution having a pH of about 3.5 for about 20 minutes, no more than about 6 percent by weight of the acid sensitive drug is dissolved by the solution.  
   
   
       23 . The orally disintegrating tablet of  claim 1 , wherein upon exposure of the sub-tablets to a solution having a pH of about 3.5 for about 20 minutes, no more than about 1 percent by weight of the acid sensitive drug is dissolved by the solution.  
   
   
       24 . The orally disintegrating tablet of  claim 1 , wherein upon exposure of the sub-tablets to a solution having a pH of about 3.5 for about 20 minutes, substantially none of the acid sensitive drug is dissolved by the solution.  
   
   
       25 . The orally disintegrating tablet of  claim 1 , comprising no more than about 50 percent by weight sub-tablets.  
   
   
       26 . A method of preparing enteric coated sub-tablets, comprising: 
 obtaining a plurality of inner cores, comprising an excipient and an acid sensitive drug in the core or in a layer over the core;    applying an inert first coating layer over the cores and drug;    applying an alkaline stabilizing layer, comprising an alkaline stabilizing agent, over the inert first coating layer; and    applying an enteric coating layer over the alkaline stabilizing layer, forming enteric coated sub-tablets.    
   
   
       27 . A method of preparing orally disintegrating tablets, comprising: 
 mixing the enteric coated sub-tablets of  claim 26  with one or more excipients, forming a tablet mixture; and    compressing a portion of the resulting tablet mixture into orally disintegrating tablets.    
   
   
       28 . The method of preparing orally disintegrating tablets of  claim 27 , wherein the orally disintegrating tablets comprise at least two sub-populations of inner cores, having different size distributions.  
   
   
       29 . The method of preparing orally disintegrating tablets of  claim 27 , wherein the amount of excipient in the tablet mixture is sufficiently great relative to the amount of enteric coated sub-tablets, and the enteric coating layer is sufficiently flexible, such that cracking of the enteric coating is minimized during compression, and upon exposure to a solution having a pH of about 3.5 for about 20 minutes, no more than about 10 percent by weight of the acid sensitive drug is dissolved by the solution.  
   
   
       30 . The method of preparing enteric coated sub-tablets of  claim 26 , wherein at least one of the layers is applied by spraying.  
   
   
       31 . The method of preparing enteric coated sub-tablets of  claim 26 , further comprising applying a layer of the acid sensitive drug over the inner cores.  
   
   
       32 . The method of preparing orally disintegrating tablets of  claim 27 , wherein the sub-tablets are present in a weight less than that of the excipients.  
   
   
       33 . The method of preparing enteric coated sub-tablets of  claim 26 , wherein the acid sensitive drug is a Benzimidazole derivative.  
   
   
       34 . The method of preparing enteric coated sub-tablets of  claim 26 , wherein the acid sensitive drug is Lansoprazole.  
   
   
       35 . An enteric coated sub-tablet, comprising: 
 an inner core, substantially free of any alkaline stabilizing agent, and comprising one or more inert core excipients;    an acid sensitive drug in, on, or over the inner core;    an inert first coating layer, substantially free of the drug and any alkaline stabilizing agent, disposed over the inner core and the drug;    an alkaline stabilizing layer, comprising an alkaline stabilizing agent, disposed over the inner core and the acid sensitive drug; and    an acid resistant enteric coating layer, disposed over the alkaline stabilizing layer.    
   
   
       36 . An orally disintegrable tablet, comprising: 
 (i) sub-tablets having an average particle diameter of at least 400 μm, wherein the sub-tablets comprise at least one benzimidazole derivative composition coated by an enteric coating layer, comprising a first component, which is an enteric coating agent, and a second component, which is a plasticizer; and    (ii) an additive; wherein    the tablet has a hardness strength greater than 6 SCU, and is orally disintegrable.    
   
   
       37 . The orally disintegrable tablet of  claim 36 , wherein the plasticizer is present in an amount of less than 15 percent by weight of the enteric coating layer, wherein, upon exposure of the sub-tablets to a solution having a pH of about 3.5 for about 20 minutes, no more than about 10 percent by weight of the acid sensitive drug is dissolved by the solution.  
   
   
       38 . The orally disintegrable tablet of  claim 36 , wherein the plasticizer is present in an amount of 10 percent or less by weight of the enteric coating layer, wherein, upon exposure of the sub-tablets to a solution having a pH of about 3.5 for about 20 minutes, no more than about 10 percent by weight of the acid sensitive drug is dissolved by the solution.  
   
   
       39 . The orally disintegrating tablet of  claim 36 , wherein the at least one benzimidazole derivative comprises Lansoprazole.  
   
   
       40 . Orally disintegrating tablets, comprising more than one enteric coated sub-tablet, mixed with one or more tablet excipients, the sub-tablets comprising at least one benzimidazole derivative; wherein the orally disintegrating tablets comprise first and second sub-populations of inner cores, the inner cores in the first sub-population having smaller diameters than the inner cores of the second population, and wherein the tablets have an average content uniformity of from about 85 to about 115 percent by weight and a relative standard deviation (RSD) of not more than 6 percent.